CN1124027A - Ureido derivatives of naphthalenephosphonic acids and process for their preparation - Google Patents

Ureido derivatives of naphthalenephosphonic acids and process for their preparation Download PDF

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CN1124027A
CN1124027A CN95190139A CN95190139A CN1124027A CN 1124027 A CN1124027 A CN 1124027A CN 95190139 A CN95190139 A CN 95190139A CN 95190139 A CN95190139 A CN 95190139A CN 1124027 A CN1124027 A CN 1124027A
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N·默格利
A·格鲁诺拉
A·洛姆巴迪·伯吉
E·佩斯梯
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Abstract

Subject of the present invention are new ureido derivatives of naphthalenephosphonic acids having formula (I), wherein each of m and n, which are the same, is an integer of 1 to 4; each of p and q, which are the same, is an integer of 1 to 3; and each of the R groups, which are the same, is a free or esterified phosphonic acid group; and the pharmaceutically acceptable salts thereof.

Description

Naphthalene phosphonic acids urea derivatives and preparation method thereof
The present invention relates to new naphthalene phosphonic acids urea derivatives, their preparation method comprises their pharmaceutical composition and they are in medically application.
The urea derivatives of many-4-amino-2-carboxyl-1-methyl-azole compounds is disclosed in International Application PCT/EP91/00014.
Have now found that new naphthalene phosphonate derivative and the very narrow new naphthalene phosphonic acids of a kind of range of choice---belong to PCT/EP91/00014 general formula scope, but not concrete therein open---have very valuable biological property.
Therefore, theme of the present invention is naphthalene phosphonic acids urea derivatives and the pharmaceutically acceptable salt thereof with following formula (I)
Figure A9519013900081
Wherein: identical m and n are respectively integer 1-4; Identical p and q are respectively integer 1-3; Identical R group is respectively the phosphonic acids of free or esterification.
Free, phosphono salinization or esterification ((HO) 2PO-yl) can be on one or two phenyl moiety of naphthyl.
The naphthyl that replaces is preferred 1-, 2-, 3-or 4-naphthyl, be typically 3-or 4-naphthyl.When naphthyl by three free, when phosphonate group esterification or salinization replaces, the phosphonic acids substituting group preferably 1-, 5-and 7-, 2-, 5-and 6-or 2-, 5-and 7-position.When they by two free, when phosphonate group esterification or salinization replaces, the phosphonic acids substituting group preferably 1-and 5-, 1-and 6-, 1-and 7-or 5-and 7-position.When they by a free, when phosphonate group esterification or salinization replaces, the phosphonic acids substituting group preferably 1-, 3-, 5-or 6-position.The present invention also comprises all possible isomer of formula (I) compound, steric isomer, their mixture and metabolite and metabolic precursor thereof or bioprecursor.
As mentioned above, the present invention also comprises the ester and the pharmaceutically acceptable salt of formula (I) acid.
Each phosphono (HO) 2PO-two acid functions group in have only one or two can be by salinization and/or esterification.
In the salt of the present invention, preferably have only one by salinization in two of each phosphono acid functions group, and in ester of the present invention, preferably have in two of each phosphono acid functions groups two esterified.
For example, the ester of formula (I) acid is alkyl and the aralkyl ester with branched-chain or straight-chain alkyl chain.C 1-C 6Alkyl and phenyl-C 1-C 6Alkyl ester is preferred, and methyl is typically arranged, ethyl, propyl group, sec.-propyl, butyl, benzyl and styroyl ester.
The example being and not being machine alkali such as the sodium of pharmaceutically acceptable salt, potassium, those salt that calcium and aluminium hydroxide form, or with organic bases such as Methionin, arginine, N-meglumin, triethylamine, trolamine, dibenzylamine, methylbenzylamine, two-(2-ethyl-hexyl)-amine, piperidines, N-ethyl piperidine, N, N-diethylamino-ethylamine, N-ethyl morpholine, β-phenylethylamine, N-benzyl-β-phenylethylamine, N-benzyl-N, those salt that N-dimethylamine and other acceptable organic amine form.Wherein sodium and sylvite are preferred.
As mentioned above, the present invention also comprises the pharmaceutically acceptable bioprecursor (also can be called prodrug) of formula (I) compound, that is, be different from above-mentioned formula (I) but transform the compound of an accepted way of doing sth (I) compound when taking to the people in vivo directly or indirectly.
Preferred formula (I) compound is that wherein m and n are 2; P and q are 2; Identical R group is free or C 1-C 6Alkyl or phenyl-C 1-C 6The phosphonate group compound of alkyl esterification and pharmaceutically acceptable salt thereof.
The preferred examples of compounds of the present invention has:
Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 5-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 6-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 6-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-2-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 5-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 6-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 6-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 5-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 6-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5-phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5-phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6-phosphonic acids of carbonyl;
Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6-phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-2,5 of carbonyl, 6-tri methylene phosphonic acid;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid;
Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid;
Two-3-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-1, the 5-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-1, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-1-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-3-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) the amino }-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid; And C 1-C 6Alkyl and phenyl-C 1-C 6Alkyl ester and pharmaceutically acceptable salt thereof.
Particularly preferred have a methyl, ethyl and benzyl ester and the present invention especially exemplified by the sodium and the sylvite of compound.
Formula (I) compound and pharmaceutically acceptable salt thereof hereinafter are also referred to as " The compounds of this invention " or " promoting agent of the present invention ".
The compounds of this invention and salt thereof can through type (II) compound or its salt and formula (III) compound prepared in reaction,
Figure A9519013900131
Wherein: n, p and R definition are as above; Wherein: each X group, can be identical or different, be good leavings group, and if desired, a formula (I) compound can be transformed into another formula (I) compound, and/or, if desired, the resulting formula of salinization (I) compound; And/or, if desired, the free acid that obtains formula (I) from the ester or the salt of formula (I) compound; And/or, if desired, the acid of esterification formula (I).
The salt of formula (II) compound can be the salt that forms with organic or inorganic alkali, such as the pharmaceutically acceptable salt of the present invention mentioned above.Preferred sodium and sylvite.
According to the implication of X, the preferred embodiment of good leavings group is a halogen atom, particularly chlorine, or other group that is not easy to replace, and as imidazolyl, triazolyl, p-nitrophenyl oxygen base or Trichlorophenoxy.
The reaction of formula (II) compound or its salt and formula (III) compound can be similar approach or carry out according to currently known methods, for example, is that the synthetic described condition of urea derivatives is carried out according to this class reaction in the organic chemistry.Preferably, when X was halogen atom such as chlorine in formula (III) compound, reaction can be carried out under about 1: 4 condition from about 1: 0.5 in the mol ratio of compound (II) or its salt and compound (III).
The preferred embodiment according to the present invention, when formula (III) when compound is phosgene, according to currently known methods, trichloromethyl carbonate or trichloromethyl chloro-formic ester can be used as phosgene source.
React preferably at organic solvent such as methylene dichloride, ethylene dichloride, chloroform, toluene or dimethyl sulfoxide (DMSO), hexamethyl phosphine triamide, N,N-DIMETHYLACETAMIDE or dimethyl formamide, or carry out in their water mixture; Or at water/diox, in water/toluene or the water/dichloromethane mixture, at organic bases such as triethylamine, diisopropylethylamine or pyridine, or carry out under mineral alkali such as sodium bicarbonate or sodium acetate or the conventional buffer reagent existence well known in the prior art.Temperature of reaction can be from-10 ℃ to 50 ℃ approximately; Reaction times was from 1 hour to 24 hours.
Formula (I) compound according to method for preparing can be used the ordinary method purifying, as silica gel or alumina column chromatography, and/or from organic solvent such as lower aliphatic alcohols or dimethyl formamide or their mixture or aqueous mixture recrystallization.
Similarly, the esterification or the salinization of formula (I) acid can be carried out with method known in the state of the art.
Formula (II) compound and salt thereof are new compounds, and are another object of the present invention.
Formula (II) compound and salt thereof can obtain according to similar approach.
Such as, formula (II) compound can adopt method through type known in the state of the art (IV) change meeting thing or the reduction of its salt to obtain, Wherein: n, p and R definition are as above.
Formula (IV) compound can be by formula V amine or its salt and the reaction of formula (VI) compound obtain,
Figure A9519013900151
Wherein: R and p definition are as above;
Figure A9519013900152
Wherein: n and X definition are as above.
The amine of formula V or its salt and the reaction of formula (VI) compound also are currently known methodss.
In addition, wherein n be 2,3 or 4 formula (IV) compound also can through type (VII) compound and amine or its salt (definition as above) polystep reaction of formula V obtain,
Figure A9519013900153
Wherein: X defines as above.This reaction can be carried out according to currently known methods, obtains formula (VIII) compound or its salt,
Figure A9519013900154
Wherein: R and p definition are as above.
Reduction obtains formula (IX) compound or its salt to formula (VIII) compound or its salt according to currently known methods,
Figure A9519013900161
Wherein: p and R definition are as above.Then obtain formula (IV) compound (definition as above) with formula (VII) compound (definition as above) reaction, wherein n is 2.If the n of the formula of requirement (IV) compound is 3 or 4, then need further reduction and acidylate.
Formula (VI) compound is a known compound or passable, such as, according to Heterocycles, Vol.27, p.1945-52 No.8 (1988) obtains.Formula (VII) compound is known product or can obtains easily according to currently known methods.The amine and the salt thereof of definition formula V as above are new compounds, and are another purposes of the present invention.
The amine of formula V or its salt can obtain by reduction-type (X) nitro-derivative or its salt according to currently known methods,
Figure A9519013900162
Wherein: R and p definition are as above.
Formula (X) nitro-derivative can pass through nitrated suitable free, list esterification or salinization-, two-or three-phosphono naphthoic acid obtain.Said free, acid esterification or salinization then also can be by by 1,2 or 3 trifluoromethanesulfonic acid ester group or halogen atom such as bromines, the naphthalene compound that iodine replaces respectively with two-C 1-C 6Alkyl, two-aryl as two-phenyl or two-aryl-alkyl as two-phenyl-C 1-C 6The alkyl phosphorous acid ester, at organic bases such as triethylamine, Diisopropylamine or pyridine and suitable catalyzer are as four-triphenylphosphine palladium (O), and platinum (O) or nickel (O) exist down, react under about 0 ℃ to 150 ℃ condition in temperature range to obtain.
By 1, the naphthalene compound that 2 or 3 trifluoromethanesulfonic acid ester groups replace can by single-, two-or the naphthalene compound that replaces of three-hydroxyl respectively with reactive trifluoromethanesulfonic acid derivative such as muriate or acid anhydride, at organic bases such as pyridine or triethylamine and organic inert solvent such as methylene dichloride, reaction obtained under ether or toluene existed.
Formula (IV), (V), (VIII), (IX) or (X) salt of compound can be the salt that forms with organic or inorganic alkali, those salt of mentioning during such as top description formula (I) compound.Preferred sodium and sylvite.
Pharmacology
According to the present invention, the new naphthalene phosphonic acids and the pharmaceutically acceptable salt thereof of formula (I) are angiogenesis inhibitors, for example, according to Folkman method (Nature, 297,307 (1982)), have been found that they have activity in the chorioallantois film test.Therefore, The compounds of this invention can be used for treating the neovascularity growth of Mammals (comprising the mankind), as in chronic inflammatory diseases, and diabetic subject's retinopathy, psoriasis, some the pathology diseases in rheumatoid arthritis and the tumor growth when harmful.Particularly in cancer therapy, The compounds of this invention can be separately or with antitumor drug such as Zorubicin, 4 ＇-iododoxorubicin, methoxyl group-morpholino-Zorubicin, Zuyeyidal, Fluracil, melphalan, endoxan, bleomycin, vinealeucoblastine(VLB) or mitomycin are used together.
It is active to have been found that The compounds of this invention also has a TNFa-neutralization, so they can be used for treating and prevent people's the known TNF of being to play any morbid state of deleterious effect.Typical this morbid state is an emaciation, septicemia patient's shock, transplant rejection disease, AIDS, cerebral malaria, rheumatoid arthritis.For example, suppress on untreated mouse LM cell by people TNFa that The compounds of this invention is the activated fact in the cellular cytoxicity activity test, prove that The compounds of this invention has TNFa-inhibition activity.Therefore, new compound of the present invention can as angiogenesis inhibitor and/or TNFa-in and promoting agent.The compounds of this invention can be used for preparing the treatment vascularization and/or prevents and/or treats the medicine that TNFa wherein plays the morbid state of deleterious effect.In these treatments were used, The compounds of this invention can pass through common administration, for example, non-enteron aisle, as intravenous injection or infusion, intramuscular, subcutaneous, part or oral administration.Dosage depends on patient's age, body weight and disease and route of administration.
For example, be about every dosage 0.5-300mg, every day 1-4 times for the suitable dosage of adult.
And, have been found that The compounds of this invention can directly be used as anti-slow virus agent, particularly anti human immune deficiency virus (HIV).For example, have been found that two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 5-di 2 ethylhexyl phosphonic acids of representative compounds carbonyl of the present invention; With two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1 of carbonyl, 7-di 2 ethylhexyl phosphonic acid is activated at J.Natl.Cancer Inst.81 in 557-586 (1989) the described tests.
Therefore the method for the The compounds of this invention by taking significant quantity to the patient can be treated slow virus infection.In this method, The compounds of this invention can be used for the infection that treatment belongs to slow virus, particularly human immunodeficiency virus, especially HIV-1 or HIV-2.
The compounds of this invention also can be used for preparing the medicine that is used for the treatment of slow virus infection.Described medicine can be used as anti-slow virus agent, for example anti-HIV-1 or HIV-2 dose.Described medicine also can be used for improving slow virus infection patient's the syndromes of being brought out by slow virus.
Particularly The compounds of this invention can be used for preparing be used for the treatment of the patient because the seropositivity that slow virus, particularly HIV infect, anxiety or pathology disease, or some induces an illness, LAS (LS) for example, AIDS related syndromes (ARC), AIDS or Kaposi sarcoma.Therefore can improve or improve patient's situation.
In these treatments were used, The compounds of this invention can pass through common administration, for example, non-enteron aisle, as intravenous injection or infusion, intramuscular, subcutaneous, part or oral administration.Intravenous injection and infusion are preferred.Dosage depends on patient's age, body weight and situation and route of administration.Compound of the present invention, two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalenes-1 of carbonyl for example, 5-di 2 ethylhexyl phosphonic acid or its pharmaceutically acceptable salt, the dosage that is fit to adult's administration is every dosage 0.5-300mg, every day 1-4 times.
The compounds of this invention can be used for treating above-mentioned pathology disease, comprises separately or almost uses composition that contains formula (I) compound or its pharmaceutically acceptable salt and the pharmaceutical composition that contains the different pharmaceutical activeconstituents simultaneously.Therefore the present invention further provides a kind of being used for the treatment of suffers from slow virus infection, particularly the patient's that infects of HIV contains formula (I) compound or its pharmaceutically acceptable salt, with as separating, in succession or continue the product of second kind of promoting agent using in conjunction with preparation.Second kind of promoting agent generally is to HIV-diseases induced influential medicine of pathogeny.
For example, The compounds of this invention can be with various promoting agents, and particularly to reversed transcriptive enzyme, biocide and antineoplastic agent or effective those compositions of their two or more mixtures use together.Interested medicine comprises non-nucleoside reverse transcriptase inhibitor, as nevi-rapine; Nucleoside derivates such as Zidovodine and didanosine; Acycloguanosine; Ribavirina; Xitix; Proteinase inhibitor; Cytokine such as IL-1, IL-2, and IL-3 or IL-4; Somatomedin; Interferon, rabbit such as α-or γ-Interferon, rabbit; Antineoplastic agent such as Zorubicin, daunorubicin, pidorubicin, 4 ＇-iododoxorubicin, methoxyl group-morpholino-Zorubicin, darubicin, Zuyeyidal, Fluracil, melphalan, ring phosphonic amide, bleomycin, vinealeucoblastine(VLB) and mitomycin; Immunomodulator, particularly immunostimulant, gamma Globulin, immunoglobulin (Ig) and monoclonal antibody product, microbiotic and antimicrobial product.Typically, biocide can comprise that penicillin is together with amino Portugal glycosides (as gentamicin, tobramycin).Yet other medicament such as cephamycin that some people know also can use.
The dosage of these medicines depends on each patient's the state of an illness.Therefore, dosage range must be suitable for patient's situation, and the particular cases of being taked in reaction and the conventional treatment mode such as corresponding treatment also must in time be regulated dose according to the variation of the state of an illness and/or other clinical setting.
Be used for pharmaceutical composition of the present invention and can contain formula (I) compound or its pharmaceutically acceptable salt, add one or more pharmaceutically acceptable vehicle and/or carrier as activeconstituents.This pharmaceutical composition can be following ordinary method preparation and with appropriate form administration on the medicine.For example, intravenous injection or infusion solution can comprise carrier such as sterilized water or preferably can be sterilized water normal isotonic saline solution form.The suspension or the solution that are used for intramuscular injection can comprise active compound and pharmaceutically acceptable carrier, sterilized water for example, sweet oil, ethyl oleate, glycols such as propylene glycol and, if desired, an amount of Xylotox.
In topical application, for example be used for the missible oil of skin diseases treatment, in the forms such as washing lotion or ointment, activeconstituents can use with conventional oily or emulsification mixed with excipients.
The Peroral solid dosage form form, for example tablet and capsule can comprise active compound and thinner such as lactose, glucose, sucrose, Mierocrystalline cellulose, W-Gum and yam starch; Lubricant such as silica, talcum powder, stearic acid, Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol; Tackiness agent such as starch, gum arabic, gelatin, methylcellulose gum, Walocel MT 20.000PV, Polyvinylpyrolidone (PVP); Dispersion agent such as starch, alginic acid, alginate, starch ethylene glycol sodium; Effervescent mixture; Tinting material; Sweeting agent; Wetting agent such as Yelkin TTS, polysorbate, lauryl sulfate (laurylsul-phates).In a word, nontoxic and parmacodynamics-less activity material all can be used for pharmaceutical preparation.Said pharmaceutical preparation can be used known method, for example, granulates by mixing, and compressing tablet, methods such as sugar coating or film-coat are made.
The following example illustrates but does not limit the present invention.
Embodiment 1
Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1,5-di 2 ethylhexyl phosphonic acid, eight ethyl esters of carbonyl
Stir down three methyl-chlorocarbonates (325mg, 1.09mmol) methylene dichloride (10ml) drips of solution be added to 3-(1-methyl-2-pyrroyl amino-4-(1-methyl-4-amino-2-pyrroyl amino))-naphthalene-1,5-ethyl diphosphonic acid (4.23g, 6.08mmol, hydrochloride) and Et 3(3.5ml, (no ethanol is in ice-cold solution 100ml) for methylene dichloride 25mmol) for N.Room temperature 34, the time after with whole solution H 2O, 1NHCl, NaHCO 3Solution washing, dry and reduction vaporization.Thick resistates flash chromatography purifying (CH on silica gel 60 2Cl 290-CH 3OH10).The solid residue acetic acid ethyl dissolution filters and drying, obtains the filbert solid crystallite (3.11g, m.p.195-205 ℃) of title compound.200 Mhz 1H NMR (DMSO-d 6): (2 are unimodal, 2H) for δ 10.45,9.88; 9.23 (d, 1H, J=1.1Hz); 8.7-8.5 (m, 2H); 8.17 (s, 1H); 8.12 (ddd, 1H, J=1.1Hz, J=7.2Hz, J=15.8Hz); 7.63 (ddd, 1H, J=3.7Hz, J=7.2Hz, J=8.6Hz); 7.35,7.27 (2 doublets, 2H, J=1.8Hz); 7.03,6.84 (2 doublets, 2H, J=1.8Hz); 4.2-3.9 (m, 8H); 3.84 3.89 (2 unimodal, 6H); 1.3-1.1 (m, 12H).(-) FAB MS (M-H) -=1344.-14-embodiment 2
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1,7-di 2 ethylhexyl phosphonic acid, eight ethyl esters of carbonyl
According to embodiment 1 described method, with 780mg 4-(1-methyl-2-pyrroyl amino-4-(1-methyl-4-amino-2-pyrroyl amino))-naphthalene-1,7-ethyl diphosphonic acid hydrochloride is made starting raw material, obtains the orange solids (270mg, 36%) of title compound.200 MHz 1H NMR (DMSO-d 6): (2 are unimodal, 2H) for δ 9.91,10.30; 8.94 (d, 1H, J=15.8Hz); 8.0-8.3 (m, 3H); 7.7-8.0 (m, 2H); 7.32,7.37 (2 doublets, 2H, J=1.8Hz); 6.84,7.03 (2 doublets, 2H, J=1.8Hz); 3.9-4.2 (m, 8H); 3.85 3.84 (2 unimodal, 6H); 1.1-1.3 (m, 12H).(-) FAB MS (M-H) -=1344. usefulness similar approach can obtain the ethyl ester of following compounds:
Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 6-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 6-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-2-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 5-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 6-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 6-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 5-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 6-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 7-di 2 ethylhexyl phosphonic acids of carbonyl;
Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5-phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5-phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6-phosphonic acids of carbonyl;
Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6-phosphonic acids of carbonyl;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-2,5 of carbonyl, 6-tri methylene phosphonic acid;
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid; With
Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid.
Embodiment 3
Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1,5-di 2 ethylhexyl phosphonic acid and the tetra-na salts thereof of carbonyl
Stir following CH with trimethylammonium bromide silane (10ml) 3CN (10ml) solution is added to eight ethyl esters (1.00g, anhydrous CH 0.74mmol) of ice-cold embodiment 1 3CN (100ml) (CH 3) 2In CO (10ml) diluting soln.Place after 24 hours the reduction vaporization organic volatile under the room temperature.Resistates is dissolved in acetone and adding (CH 3) 2The H of CO (10ml) dilution 2O (500mg) stirred after 4 hours, leached isolating solid crystallite, used acetone, methyl alcohol, and ether washing and vacuum-drying obtain title acid (779mg).
Ultimate analysis:
Calculated value %:C48.22, H3.96, N12.50, O24.27, P11.05
Measured value %:C44.46, H4.26, N11.18, P9.48200MHz 1H NMR (DMSO-d 6, T=50 ℃): (2 are unimodal, 2H) for δ 9.74,10.23; 9.07 (s, 1H); 8.72 (d, 1H, J=8.5Hz); 8.47 (dd, 1H, J=1.9Hz, J=16.9Hz); 8.05 (dd, 1H, J=7.1Hz, J=15.6Hz); 8.01 (s, 1H); 7.48 (ddd, 1H, J=3.2Hz, J=7.1Hz, J=8.5Hz); 6.83,7.00,7.25,7.31 (4 doublets, 4H, J=1.8Hz); 3.85 3.89 (2 unimodal, 6H).
(650mg 0.58mmol) is dissolved in H with the acid that obtains thus 2O (50ml) also uses NaHCO 3(195mg 2.32mmol) is neutralized to pH6.5-7.Filtering solution is evaporated to small volume and freeze-drying, obtains filbert crystallite salt.Ultimate analysis: C 45H 40N 10Na 4O 17P 4(1208.70), measured value (calculated value) %:
N9.88 (11.59) %; Drying forfeiture (100 ℃) 12.75%.200MHz 1H NMR (D 2O+NaOD): δ 8.76 (m, 2H); 8.02 (m, 2H); 7.47 (m, 1H); 6.61,6.84,6.99,7.22 (4 doublets, 4H, J=1.9Hz); 3.76 3.84 (2 unimodal, 6H).Embodiment 4
Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1,7-di 2 ethylhexyl phosphonic acid and the tetra-na salts thereof of carbonyl
According to embodiment 3 described methods, with two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1 of 197mg carbonyl, 7-di 2 ethylhexyl phosphonic acid, eight ethyl esters are made starting raw material, obtain the orange solids (160mg, 98%) of title acid.200MHz 1H NMR (DMSO-d 6, T=50 ℃): (2 are unimodal, 2H) for δ 9.78,10.05; 9.13 (d, 1H, J=15.6Hz); 8.0-8.2 (m, 3H); 7.6-7.9 (m, 2H); 6.85,7.01,7.29,7.33 (4 doublets, 4H, J=1.8Hz); 3.85 3.86 (2 unimodal, 6H).
Use NaHCO 3Neutralize, obtain the filbert solid (163mg, 98%) of title tetra-na salt.200MHz 1H NMR (D 2O+NaOD, T=50 ℃): δ 9.04 (d, 1H, J=14Hz); 8.03 (dd, 1H, J=7.4Hz, J=13.7Hz); 7.7-8.0 (m, 2H); 7.34 (dd, 1H, J=2.3Hz, J=7.4Hz); 6.78 6.99 (2 unimodal, 2H); 3.80 3.85 (2 unimodal, 6H).Ultimate analysis: C 45H 40N 10Na 4O 17P 4Calculated value %:C44.72, H3.33, N11.59
Measured value %:C34.33, H3.50, N8.58
Obtain the free acid and the sodium salt of following compounds with similar approach: two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 6-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 6-di 2 ethylhexyl phosphonic acids of carbonyl; Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-2-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 5-di 2 ethylhexyl phosphonic acids of carbonyl; Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 6-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 6-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 5-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 6-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5-phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5-phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6-phosphonic acids of carbonyl; Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6-phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-2,5 of carbonyl, 6-tri methylene phosphonic acid; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid; Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid.Embodiment 5
3-(1-methyl-2-pyrroyl amino-4-(1-methyl-4-amino-2-pyrroyl amino))-naphthalene-1,5-ethyl diphosphonic acid hydrochloride
To be dissolved in 3 in the methyl alcohol (350ml) and the 1N HCl aqueous solution (7.0ml)-(1-methyl-2-pyrroyl amino-4-(1-methyl-4-nitro-2-pyrroyl amino))-naphthalene-1,5-ethyl diphosphonic acid (4.50g, 6.52mmol) with 5%Pd/c (500mg) in the PARR instrument hydrogenation up to H 2Absorption stops.Behind the separating catalyst, reduction vaporization methyl alcohol.With the solid crystallite filtration that resistates is dissolved in ether and separation is obtained, washing at 60 ℃ of drying under reduced pressure, obtains the hydrochloride (4.43g, 96%) of title compound.Ultimate analysis: C 30H 40ClN 5O 8P 2Measured value (calculated value) %:C49.93 (51.76), H5.93 (5.79), Cl5.00 (5.09), N9.61 (10.06) (-) FAB MS:(M-H) -=658400MHz 1(2 unimodal, 2H) for H NMR: δ 10.13,10.46; 9.85 (bs, 3H); 9.23 (s, 1H); 8.60 (d, 1H, J=8.5Hz); 8.56 (dd, 1H, J=2.0Hz, J=17.3Hz); 8.12 (dd, 1H, J=7.3Hz, J=17.0Hz); 7.64 (ddd, 1H, J=3.5Hz, J=7.3Hz, J=8.5Hz); 7.26,7.36 (2 doublets, 2, J=1.8Hz); 7,00,7.10 (2 doublets, 2H, J=2.0Hz); 4.00-4.2 (m, 8H); 3.89 (s, 6H); 1.2-1.3 (m, 12H).Embodiment 6
4-(1-methyl-2-pyrroyl amino-4-(1-methyl-4-amino-2-pyrroyl amino))-naphthalene-1,7-ethyl diphosphonic acid hydrochloride
Press embodiment 5 described methods 1.0g 4-(1-methyl-2-pyrroyl amino-4-(1-methyl-4-nitro-2-pyrroyl amino))-naphthalenes-1,7-ethyl diphosphonic acid obtains the brown solid (0.95g, 94%) of title product as starting raw material.80MHz? 1H?NMR(DMSO-d 6)：δ10.3(s，1H)；10.15(s，1H)；10.1(br，3H)；8.95(d，1H)；7.65-8.4(m，4H)；7.3-7.4(m，2H)；7.0-7.15(m，2H)；3.9-4.3(m，8H)；3.9(s，3H)；3.85(s，3H)；1.1-1.4(m，12H)。Embodiment 7
3-(1-methyl-2-pyrroyl amino-4-(1-methyl-4-nitro-2-pyrroyl amino))-naphthalene-1,5-ethyl diphosphonic acid
The ice bath cooling conditions is down with 1-methyl-4-nitro-2-pyrroles carboxylic acid chloride (1.41g, 15ml CH 7.5mmol) 2Cl 2Dropwise handle CH 2Cl 2(no ethanol, 100ml) in as 3 of hydrochloride-(1-methyl-4-amino-2-pyrroyl amino)-naphthalene-1,5-ethyl diphosphonic acid (7.3mmol) and triethylamine (3.5ml, 25mmol).In ice, successively respectively placed 1 hour then, with acid and NaHCO with room temperature 3The solution washing organic phase, dry (Na 2SO 4) and reduction vaporization.Scraping the thick resistates that is dissolved in ethanol (20ml) again forms to cause crystallization; (20ml) finishes crystallization with ether, leaches isolating crystalline yellow solid, uses ethanol: ether mixture washing in 1: 1 at 50 ℃ of drying under reduced pressure, obtains title compound (4.50g, m.p.163-168 ℃, 89%).Ultimate analysis: C 30H 37N 5O 10P 2Measured value (calculated value) %:N9.85 (10.16) (-) FAB MS (M-H) -=688.400MHz 1H NMR (DMSO-d 6): (2 are unimodal, 2H) for δ 10.34,10.49; 9.23 (s, 1H); 8.61 (d, 1H, J=8.4Hz); 8.57 (dd, 1H, J=2.0Hz, J=17.6Hz); 8.12 (dd, 1H, J=7.0Hz, J=16.1Hz); 7.63 (ddd, 1H, J=4.2Hz, J=7.0Hz, J=8.4Hz); 7.60,8.19 (2 doublets, 2H, J=1.8Hz); 7.26,7.37 (2 doublets, 2H, J=1.8Hz); 4.0-4.2 (m, 8H); 3.90 3.96 (2 unimodal, 6H); 1.1-1.3 (m, 12H).Embodiment 8
4-(1-methyl-2-pyrroyl amino-4-(1-methyl-4-nitro-2-pyrroyl amino))-naphthalene-1,7-ethyl diphosphonic acid
Press embodiment 7 described methods and obtain 1.89g title compound (85%) as starting raw material with 1.84g 4-(1-methyl-4-amino-2-pyrroyl amino)-naphthalene-1,7-pyrodust hydrochloride.200MHz 1H NMR (DMSO-d 6): (2 are unimodal, 2H) for δ 10.34,10.37; 8.94 (d, 1H, J=16.0Hz); 8.1-8.3 (m, 2H); 7.7-7.9 (m, 2H); 7.62,8.20 (2 doublets, 2H, J=2.1Hz); 7.32,7.40 (2 doublets, 2H, J=1.9Hz); 3.9-4.2 (m, 8H); 3.86 3.97 (2 unimodal, 6H); 1.1-1,3 (m, 12H).(-)FAB?Ms(M-H) -＝688。Embodiment 9
3-(1-methyl-4-amino-2-pyrroyl amino)-naphthalene-1,5-ethyl diphosphonic acid
To be dissolved in 3 among methyl alcohol (150ml) and the 1N HCl (7.5ml)-(1-methyl-4-nitro-2-pyrroyl amino)-naphthalene-1,5-ethyl diphosphonic acid (4.15g, 7.31mmol) in the presence of 5%Pd/C in the PARR instrument hydrogenation up to H 2Absorption stops.Behind filtering catalyzer on the flocculating aids, reduction vaporization methyl alcohol, vacuum-drying resistates and need not to be further purified just and can carry out acidylate.80MHz? 1H?NMR(CDCl 3)：δ9.6(s，1H)；9.05(m，1H)；8.67(dd，1H，J＝1.9Hz，J＝17.6Hz)；8.67(d，1H，J＝8.6Hz)；8.12(dd，1H，J＝6.5Hz，J＝15.9Hz)；7.75(s，1H)；7.55(m，1H)；6.87(s，1H)；3.9-4.4(m，8H)；3.75(s，3H)；1.0-1.4(m，12H)。Embodiment 10
4-(1-methyl-4-amino-2-pyrroyl amino)-naphthalene-1,7-ethyl diphosphonic acid hydrochloride
Press embodiment 9 described methods obtain the 1.84g title product as starting raw material with 1.89g 4-(1-methyl-4-nitro-2-pyrroyl amino)-naphthalene-1,7-ethyl diphosphonic acid brown solid (96%).80MHz? 1H?NMR(DMSO-d 6)：δ10.45(s，1H)；10.2(br，3H)；8.95(d，1H)，7.65-8.4(m，4H)；7.2-7.35(m，2H)；3.8-4.4(m，llH)；1.1-1.4(m，12H)。Embodiment 11
3-(1-methyl-4-nitro-2-pyrroyl amino)-naphthalene-l, 5-ethyl diphosphonic acid
With 1-methyl-4-nitro-2-pyrroles carboxylic acid chloride (1.89g, CH 10mmol) 2Cl 2(15ml) drips of solution be added to 3 ice-cold-amino-naphthalene-1,5-ethyl diphosphonic acid hydrochloride semihydrate (3.75mg, 8.14mmol) and triethylamine (3.75ml, CH 27mmol) 2Cl 2(no ethanol is 60ml) in the solution.Room temperature was placed after 4 hours, organic phase H 2O, 1N HCl then uses 5%NaHCO 3Washing, dry (Na 2SO 4) and reduction vaporization to small volume, then on silica gel 60 with purified by flash chromatography (CH 2Cl 295:CH 3OH5).With the solid residue ether dissolution, filter after drying, obtain title compound (4.17g, m.p.250.5-252.5 ℃, 90%).Ultimate analysis:
C 24H 3LN 3O 9P 2Measured value (calculated value) %:C 24H 31N 3O 9P 2Measured value (calculated value) %:
C50.87(50.79)，H5.53(5.51)，N7.35(7.40)。80MHz? 1H?NMR(CDCl 3)：δ9.77(s，1H)；9.23(d，1H，J＝2.2Hz)；8.65(dd，1H，J＝1.4Hz，J＝8.4Hz)；8.55(dd，1H，J＝2.2Hz，J＝17.4Hz)；8.13(ddd，1H，J＝1.4Hz，J＝7.3Hz，J＝16.0Hz)；7.3-7.7(m，3H)；3.9-4.5(m，8H)；3.87(s，3H)；1.1-1.6(m，12H)。EI?MS(M) 1＝567。Embodiment 12
4-(1-methyl-4-nitro-2-pyrroyl amino)-naphthalene-1,7-ethyl diphosphonic acid
Press embodiment 11 described methods and obtain the thick title product of 2.63g with 2.0g 1,7-ethyl diphosphonic acid-4-amino naphthalenes hydrochloride as initial compounds, recrystallization from benzene obtains 1.90g white solid crystallite (m.p.204-205 ℃, 76%) then.200MHz 1H NMR (CDCl 3): δ 9.89 (s, 1H); 8.85 (dd, 1, J=1.5Hz, J=15.9Hz); 7.9-8.1 (m, 2H); 7.79 (dd, 1H, J=3.4Hz, J=7.9Hz); 7.67,8.05 (2 doublets, 2H, J=1.8Hz); 7.52 (ddd, 1H, J=1.5Hz, J=8.7Hz, J=11.6Hz): 4.0-4.3 (m, 8H); 4.04 (s, 3H); 1.2-1.4 (m, 12H).EI?MS(M) +＝567。Embodiment 13
3-amino naphthalenes-1,5-ethyl diphosphonic acid
To be dissolved in 3-nitro-naphthalene-1,5-ethyl diphosphonic acid in the methyl alcohol (150ml) and the 1N HCl aqueous solution (10m) in the presence of 5%Pd/C in the PARR instrument with H 2Stir up to H together 2Stop to absorb.Behind filtering catalyzer on the flocculating aids, reduction vaporization methyl alcohol; Resistates is stirred with ethanol (10ml) and ether (50ml), then isolating crystalline solid is filtered, the washing after drying obtains with the isolating title product of hydrochloride semihydrate (3.78g decomposes 230-240 ℃, 91%).Ultimate analysis: C 18H 28CLNO 6P 2.0.5H 2O measured value (calculated value) %:
C46.99(4?6.91)；H6.32(6.3?4)；N3.02(3.04)。80MHz? 1H?NMR(CDCl 3)：δ8.3(bs，3H)；9.03(d，1H，J＝2.1Hz)；8.77(d，1H，J＝8.5Hz)；8.50(dd，1H，J＝2.1Hz，J＝16.6Hz)；8.26(ddd，1H，J＝1.3Hz，J＝7.2Hz，J＝15.6Hz)；7.65(ddd，1H，J＝3.9Hz，J＝7.2Hz，J＝8.5Hz)；3.9-4.5(m，8H)；1.3-1.5(m，12H)。Embodiment 14
1,7-ethyl diphosphonic acid-4-amino naphthalenes hydrochloride
Press embodiment 13 described methods and obtain the faint yellow solid (94%) of 2.6g title product with 2.7g 1,7-ethyl diphosphonic acid-4-nitro-naphthalene.80MHz? 1H?NMR(CDCl 3+D 2O)：δ8.9(d，1H)；8.1(dd，1H)；7.65-7.95(m，2H)；6.85(dd，1H)；3.9-4.4(m，8H)；1.2-1.5(m，12H)。Embodiment 15
3-nitro-naphthalene-1,5-ethyl diphosphonic acid
(10.21g, 25.5mmol) batch dissolution is in ice-cold 96%H with naphthalene-1,5-ethyl diphosphonic acid 2SO 4In, drip sulfo group nitrate mixture (2.5ml90%HNO after 15 minutes 37.5ml96%H 2SO 4).After ice-cooled 30 minutes, pour reaction mixture into ice-H 2The O mixture is used ethyl acetate extraction.Organic extract liquid H 2O, NaH-CO 3Solution washing, drying is evaporated to 20ml, with the dilution of 30ml hexanaphthene.After ice-cooled, isolating crystalline solid is filtered, the washing after drying obtains title compound (8.48g, m.p.117-118.5 ℃, 74.7%).Ultimate analysis: C 18H 25NO 8P 2Measured value (calculated value) %:
C48.31(48.54)，H5.64(5.66)，N2.98(3.14)。80MHz? 1H?NMR(CDCl 3)：δ9.75(dd，1H，J＝2.3Hz，J＝1.0Hz)；8.97(dd，1H，J＝2.3Hz，J＝16.6Hz)；8.93(m，1H)；8.46(ddd，1H，J＝1.3Hz，J＝7.1Hz，J＝15.9Hz)；7.85(ddd，1H，J＝3.6Hz，J＝7.1Hz，J＝8.4Hz)；3.9-4.6(m，8H)；1.38(t，12H，J＝7.2Hz)；EI?MS(M) +＝445。Embodiment 16
1,7-ethyl diphosphonic acid-4-nitro-naphthalene
At N 2Down, with 1,7-two triflate-4-nitro-naphthalene (266mg, 0.57mmol), diethyl phosphite (315mg, 2.28mmol) and triethylamine (345mg 3.42mmol) is dissolved in 20ml CH 3Among the CN.A collection of adding tetrakis triphenylphosphine palladium (O) (50mg, 0.043mmol), and with gained mixture backflow 2 hours.Cooling back removal of solvent under reduced pressure is dissolved in ethyl acetate again with resistates, uses H 2O, dilute hydrochloric acid, NaH-CO 3Solution and H 2The O washing, dry and vacuum-evaporation.With column chromatography purifying (SiO 2, ethyl acetate/methanol 96/4 is as eluent), obtain the yellow solid (198mg, m.p.54-57 ℃, 78%) of title product.80MHz? 1H?NMR(CDCI 3)：δ9.15(dd，1H)；7.9-8.6(m，4H)；4.0-4.5(m，8H)；1.1-1.5(m，12H)。Embodiment 17
Naphthalene-1,5-ethyl diphosphonic acid
With the anhydrous N of 50ml, naphthalene in N-dimethyl formamide-1, and 5-two triflate (16.46g, 40mmol) (pyridine with trifluoromethanesulfanhydride anhydride handles 1,5-dihydroxy naphthlene makes, m.p.112-113 ℃), and diethyl phosphite (13.81g, 100mmol), anhydrous N, N-diisopropylethylamine (15.51g, 120mmol) and tetrakis triphenylphosphine palladium (O) (1.00g, 0.86mmol) 95-100 ℃ the heating 3 hours.After the cooling, pour reaction mixture into H 2Among the O, use ethyl acetate extraction.Organic extract liquid H 2O, diluted acid, NaHCO 3Solution and H 2The O washing, dry (Na 2SO 4), be evaporated to 50ml, with the dilution of 25ml ether.After the cooling, isolating crystalline solid is filtered, with the ether washing, drying obtains title product (12.23g, m.p.169-171 ℃, 76.4%).Ultimate analysis: C 18H 26O 6P 2Measured value (calculated value) %:C53.74 (54.00), H6.53 (6.55).EI?MS(M) +＝400。80MHz? 1H?NMR(CDCl 3)：δ8.82(dd，2H，J＝8.7Hz，J＝1.2Hz)；8.30(ddd，2H，J＝1.2Hz，J＝6.9Hz，J＝15.6Hz)；7.65(ddd，2H，J＝3.9Hz，J＝6.9Hz，J＝8.7Hz)；3.9-4.5(m，8H)；1.32(t，12H，J＝7.2Hz)。Embodiment 18
1,7-two triflate-4-nitro-naphthalenes
With naphthalene-1, (2.12g, 5mmol) (handling 1,7-dihydroxy naphthlene with the pyridine of trifluoromethanesulfanhydride anhydride makes) branch short run adds in-10 ℃ of (ice-salt bath) refrigerative 90% nitric acid 7-two triflate.The gained reaction mixture was stirred 30 minutes, pour in the 100g ice/water then and use extracted with diethyl ether.Organic extract liquid H 2O, NaHCO 3Solution and H 2The O washing, dry then.Removal of solvent under reduced pressure, resistates flash chromatography (SiO 2) purifying.With cyclohexane/ethyl acetate 90/10 wash-out, obtain the faint yellow crystalline solid (1.96g, 83%) of title product.80MHz? 1H?NMR(CDCl 3)：δ8.8(d，1H，J＝9.6Hz)；8.3(d，1H，J＝8.8Hz)；8.1(d，1H，J＝2.8Hz)；7.65-7.85(m，2H)。Embodiment 19
Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1,5-di 2 ethylhexyl phosphonic acid, eight ethyl esters of carbonyl
To be dissolved in dimethyl formamide as 3 of hydrochloride-(1-methyl-2-pyrroyl amino-4-(1-methyl-4-amino-2-pyrroyl amino))-naphthalene-1,5-ethyl diphosphonic acid (920mg, 1.32mmol) and 4,4 ＇-carbonyl is two-and (250mg 0.62mmol) heats at 50-70 ℃ and all dissolved until imdazole derivatives in 3 hours (2-(N-imidazoles carbonyl)-4-amino-1-methylpyrrole).The reduction vaporization dimethyl formamide; Resistates is dissolved in CH 2Cl 2, use H 2O, 0.5N HCl, 5%NaHCO 3Solution, saturated NaCl solution washing, dry (Na 2SO 4) and reduction vaporization.Thick resistates is used purified by flash chromatography on silica gel, use CH 2Cl 2/ EtOH85/15 wash-out obtains the light brown crystalline solid (710mg, 68%) of title compound.200MHz 1H NMR (DMSO-d 6): δ 10.46,10.00, and 9.83 (3 are unimodal, 3H); 9.24 (s, 1H); 8.7-8.5 (m, 2H); 8.21 (s, 1H); 8.12 (ddd, 1H, J=1.2Hz, J=7.1Hz, J=16.8Hz); 7.64 (ddd, 1H, J=3.7Hz, J=7.1Hz, J=8.7Hz); 7.35,7.28,7.24,7.08,7.02,6.81 (6 doublets, 6, J=1.7Hz); 4.3-4.0 (m, 8H); 3.89 3.86,3.83 (3 unimodal, 9H); 1.4-1.2 (m, 12H).(-)FAB?MS(M-H) -＝1587。Embodiment 20
Two-4-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-1,7-di 2 ethylhexyl phosphonic acid, eight ethyl esters of carbonyl
With compound 4-(1-methyl-2-pyrroyl amino-4-(1-methyl-4-amino-2-pyrroyl amino))-naphthalene-1,7-ethyl diphosphonic acid hydrochloride (172mg, 2.48mmol) and 4,4 ＇-carbonyl is two-(2-(N-imidazoles carbonyl)-4-amino-1-methylpyrrole) (503mg, 1.24mmol) be suspended in the anhydrous dimethyl formamide (30ml), whole solution was stirred 2.5 hours at 70 ℃.Solvent evaporated under reduced pressure is separated resistates in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, make eluent with methylene dichloride/ethanol 4/1, obtains the faint yellow solid (600mg) of title product.80-MHz 1H NMR (DMSO-d 6): δ 1.25 (m, 12H, 4-CH 2CH 3); 3.7-4.3 (m, 17H, 4-CH 2CH 3+ 3-CH 3); 6.8,7.0,7.1,7.2 (4 doublets, 4H, pyrroles); (7.35 s, 2H, pyrroles); (7.6-8.4 m, 5H, 2+3+5+6+NHCO urea); (8.95 d, 1H, 8); 9.8,10.0,10.25 (3 are unimodal, 3H, 3-CONH).(-)FAB?MS(M-H) -＝1588。
Can obtain the free acid and the sodium salt of following compounds with similar approach: two-1-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-3-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) the amino }-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid.Embodiment 21
Two-3-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-1,5-di 2 ethylhexyl phosphonic acid and the tetra-na salts of carbonyl
(3.9ml 30mmol) handles CH with trimethylammonium bromide silane to press embodiment 3 described methods 2Cl 2Eight ethyl ester compounds that embodiment 19 in (50ml, no ethanol) obtains (620mg, 0.39mmol).Obtain the light brown crystallization salt solution (540mg) of title acid after the processing.200-MHz 1H NMR (DMSO-d 6): δ 10.32,9.98, and 9.83 (3 are unimodal, 3H); 9.08 (s, 1H); 8.68 (d, 1H, J=8.9Hz); 8.48 (dd, 1H, J=2.2Hz, J=17.1Hz); 8.1 (bs, 1H); 8.04 (ddd, 1H, J=1.3Hz, J=7.1Hz, J=15.8Hz); 7.50,7.26,7.24,7.06,7.01,6.81 (6 doublets, 6H, J=1.7Hz); 3.88 3.86,3.83 3 unimodal, 9H).(-)FAB?MS(M-H) -＝1363。
(520mg) is dissolved in H with gained acid 2Also be neutralized to pH6.0 among the O (50ml) with 0.5N NaOH.Filtering solution is evaporated to small volume, and freeze-drying obtains light brown salt crystallite.Ultimate analysis: C 57H 52N 14Na 4O 19P 4(1452.95), measured value (calculated value) %:
C39.08(47.11)；H5.11(3.61)；N11.08(13.50)；
Drying forfeiture 16.00.400-MHz 1H NMR (DMSO-d 6): identical with free acid.(-)FAB?MS(M-H) -＝1451，(M-Na) -＝1429。Embodiment 22
Two-4-{ (4-({ 4-((4-amino-pyrroles-1-methylpyrrole-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-1,7-di 2 ethylhexyl phosphonic acid and the tetra-na salts of carbonyl
With two-4-{ (4-({ 4-((4-amino-1-methylpyrrole-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) the amino }-naphthalenes-1 of compound carbonyl, 7-di 2 ethylhexyl phosphonic acid, eight ethyl ester (578mg, 0.364mmol) be dissolved in anhydrous methylene chloride (75ml), dripping bromine trimethyl silane when under 0 ℃ of nitrogen, stirring (4.54ml, 35mmol).Whole solution was stirred 1 hour at 0 ℃, then stirring at room 66 hours.Evaporating solvent is suspended to resistates in the acetone (100ml) and water/acetone 1/5 (6ml) is handled.Whole solution stirring at room 3 hours, is filtered then, obtain the free acid (490mg, brown solid) of title product.80-MHz 1H NMR (DMSO-d 6): δ 3.7-4.0 (m, 9H, 3-CH 3); 6.8,7.0,7.1,7.2 (4 doublets, 4H, pyrroles; (7.35 m, 2H, pyrroles); (7.6-8.3 m, 5H, 2+3+5+6+NHCO urea); (9.1 d, 1H, 8); 9.8,10.0,10.15 (3 are unimodal, 3H, 3-CONH).(-)FAB?MS(M-H) -＝1363。
(480mg 0.352mmol) is dissolved in the water (20ml) also with sodium bicarbonate (118mg, 1.406mmol) neutralization with gained acid.Filter tetra-na salt solution and freeze-drying, obtain the soft beige solid (515mg) of title compound.400-MHz 1H NMR (DMSO-d 6+ CF 3COOH): δ 3.84,3.86,3.87 (3 are unimodal, 9H, 3-NCH3); 6.81,7.03,7.10,7.24,7.32,7.37 (6 doublets, J=1.7Hz, 6H, pyrroles); (7.72 dd, J=2.4Hz, J=7.9Hz, 1H, 3); (7.77 m, 1H, 6); 8.10 (m, 2H, 5+2); (8.3 bs, 1H, NHCO urea); (9.10 d, J=15.4,1H, 8); 9.85,10.02,10.19 (3 are unimodal, 3H, 3-CONH).(-)FAB?MS(M+H-2Na) -＝1407。
Can obtain the free acid and the sodium salt of following compounds with similar approach: two-1-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; With two-3-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) the amino }-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid.Embodiment 23
Two-4-amino-1-methylpyrrole-2-carboxylic acids of 4-4 ＇-carbonyl and 4-4 ＇-carbonyl pair-(2-(N-imidazoles carbonyl)-4-amino-1-methylpyrazole)
Stir and will be dissolved in 1 ice-cold the time, two-(trichloromethyl) carbonate solution (1.25g in the 4 — dioxs (10ml), 4.2mmol) be added drop-wise to 4-amino-1-methylpyrrole-2-carboxylic acid (4.00g, 22.6mmol, hydrochloride), (7.56g is in water 90m-mol) (75ml) and 1,4 — diox (25ml) solution for sodium bicarbonate.Reaction mixture is acidified to pH1-2 with dilute hydrochloric acid,, uses H sedimentary white solid filtering 2O washs after drying, obtains title acid (3.89g, 95%). 1H NMR (DMSO-d 6): (b, 1H is with D for δ 12.1 2The O exchange); 8.2 (s, 1H is with D 2The O exchange); 7.12 (d, 1H); 6.62 (d, 1H); 3.80 (s, 3H).
With N, (5.80g, 32.6mmol) add above-mentioned acid (3.29g is in dimethyl formamide 10.75mmol) (50ml) in batches for N ＇-carbonyl dimidazoles in stirring at room.With the precipitated solid filtering, use dimethyl formamide and Et after 4 hours 2The O washing, drying obtains title compound (3.90g, 90%). 1H?NMR(DMSO-d 6)：δ8.75(bs，1H)；8.25(m，1H)；7.70(t，1H)；7.52(d，1H)；7.13(m，1H)；6.80(d，1H)；3.90(s，3H)。Embodiment 24
Intramuscular injection 40mg/ml
With two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1 of 40g carbonyl, 5-di 2 ethylhexyl phosphonic acid tetra-na salt is dissolved in the water for injection (1000ml), and be encapsulated in 1-10ml ampoule, can be made into injectable pharmaceutical preparation.

Claims (13)

1. formula (I) compound and pharmaceutically acceptable salt thereof Wherein: identical m and n are respectively integers 1-4; Identical p and q are respectively integers 1-3; Identical R group is respectively the phosphonate group of free or esterification.
2. the ester of formula (I) compound of claim 1 definition, wherein said ester is C 1-C 6Alkyl or phenyl-C 1-C 6Alkyl ester.
3. formula (I) compound and the pharmaceutically acceptable salt thereof of claim 1 definition, wherein m and n are 2; P and q are 2; Identical R group is free or C 1-C 6Alkyl or phenyl-C 1-C 6The phosphonate group of alkyl esterification.
4. one kind is selected from following one group compound: two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 5-di 2 ethylhexyl phosphonic acids of=carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 6-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 6-di 2 ethylhexyl phosphonic acids of carbonyl; Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-2-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-1, the 5-di 2 ethylhexyl phosphonic acids of carbonyl; Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 6-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5, the 6-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 5-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 6-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-2, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5-phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-5-phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6-phosphonic acids of carbonyl; Two-1-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-naphthalene-6-phosphonic acids of carbonyl; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-2,5 of carbonyl, 6-tri methylene phosphonic acid; Two-4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid; Two-3-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } the amino)-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid; Two-3-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-1, the 5-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-1, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-1-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-4-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) amino }-naphthalene-5, the 7-di 2 ethylhexyl phosphonic acids of carbonyl; Two-3-{ (4-({ 4-((4-amino-pyrroles-1-methyl-2-carbonyl) amino)-1-methylpyrrole-2-carbonyl } amino)-1-methylpyrrole-2-carbonyl) the amino }-naphthalenes-1,5 of carbonyl, 7-tri methylene phosphonic acid; And C 1-C 6Alkyl and phenyl-C 1-C 6Alkyl ester and pharmaceutically acceptable salt.
5. formula (I) compound of a claim 1 definition and the preparation method of salt thereof, this method comprises that formula (II) compound or its salt and formula (III) compound react,
Figure A9519013900051
Wherein: n, p and R such as claim 1 definition;
Figure A9519013900052
Wherein: each X group, can be identical or different, be good leavings group, and a formula (I) compound can be transformed into another formula (I) compound if desired, and/or, if desired, salinization formula (I) compound; And/or, if desired, obtain its free acid from the ester or the salt of formula (I) compound; And/or, if desired, the acid of esterification formula (I).
6. pharmaceutical composition, this pharmaceutical composition contain pharmaceutically acceptable carrier and/or thinner and as the claim 1-4 of active compound formula (I) compound or its pharmaceutically acceptable salt in any.
7. according to formula (I) compound or its pharmaceutically acceptable salt of claim 1-4 in any, as angiogenesis inhibitor.
8. according to formula (I) compound or its pharmaceutically acceptable salt of claim 1-4 in any, as among TNF-α and promoting agent.
9. according to formula (I) compound or its pharmaceutically acceptable salt of claim 1-4 in any, as anti-slow virus agent.
10. formula (1I) compound and salt thereof,
Figure A9519013900061
Wherein: n is an integer 1-4; P is an integer 1-3; Each R group is the phosphonate group of free or esterification.
11. the preparation method of formula (II) compound or its salt of claim 10 definition, this method comprises reduction-type (IV) compound or its salt,
Figure A9519013900062
Wherein: n, p and R such as claim 10 definition.
12. formula V compound and salt thereof, Wherein: p is that integer 1-3 and each R group are the phosphonate groups of free or esterification.
13. the preparation method of the formula V compound or its salt of claim 12 definition, this method comprises reduction-type (X) compound or its salt,
Figure A9519013900072
Wherein: R and p such as claim 12 definition.
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AU678704B2 (en) 1997-06-05
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ATE190312T1 (en) 2000-03-15
FI955180A (en) 1995-10-30
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EP0696287B1 (en) 2000-03-08
MX9504381A (en) 1997-01-31
WO1995023806A3 (en) 1995-09-28
US5700788A (en) 1997-12-23
DK0696287T3 (en) 2000-07-31
HU9503433D0 (en) 1996-01-29
PT696287E (en) 2000-08-31
DE69515390T2 (en) 2000-09-21
GB9403909D0 (en) 1994-04-20
CN1061050C (en) 2001-01-24
IL112716A0 (en) 1995-05-26
EP0696287A1 (en) 1996-02-14
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CA2160250A1 (en) 1995-09-08
MY130125A (en) 2007-06-29
GR3033356T3 (en) 2000-09-29
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FI955180A0 (en) 1995-10-30
NO954346D0 (en) 1995-10-30
TW290547B (en) 1996-11-11
PL311339A1 (en) 1996-02-05
WO1995023806A2 (en) 1995-09-08
NO954346L (en) 1995-10-30
ZA951653B (en) 1995-12-08
KR960701881A (en) 1996-03-28
AU1848895A (en) 1995-09-18
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